Cellular signalling最新文献

Angiogenesis plays a pivotal role in the progression and metastasis of solid cancers, including prostate cancer (PCa). While small extracellular vesicles derived from PCa cell lines induce a proangiogenic phenotype in vascular endothelial cells, the contribution of plasma exosomes from patients with PCa to this process remains unclear. Here, we successfully extracted and characterized plasma exosomes. Notably, a ring of PKH67-labeled exosomes was observed around the HUVEC nucleus using fluorescence microscopy, indicating the uptake of exosomes by HUVEC. At the cellular level, PCa plasma exosomes enhanced angiogenesis, proliferation, invasion, and migration of HUVEC cells. Moreover, PCa plasma exosomes promoted angiogenesis and aortic sprouting. MicroRNAs are the most common genetic material in exosomes, and to identify miRNAs associated with the angiogenic response, we performed small RNA sequencing followed by RT-qPCR and bioinformatics analysis. These analyses revealed distinct miRNA profiles in plasma exosomes from patients with PCa compared to healthy individuals. Notably, hsa-miR-184 emerged as a potential regulator implicated in the proangiogenic effects of PCa plasma exosomes.

Thousand and one amino-acid protein kinases(TAOKs), as a key member of the mitogen-activated protein kinase (MAPK) cascade, has recently attracted widespread attention in the field of anti-cancer research. There are three members of this subfamily: TAOK1, TAOK2, and TAOK3. Studies have shown that members of the TAOK family participate in regulating cell proliferation, apoptosis, migration, and invasion through various pathways, thereby playing an important role in tumorigenesis and progression. This review summarizes the functions of TAOK kinases in tumor cell signal transduction, cell cycle regulation, and the tumor microenvironment, with a particular emphasis on its potential as a target for anti-cancer drugs. Future research will further elucidate the specific mechanisms of action of TAOK kinase in different types of tumors and explore its clinical application prospects.

Information on the potential role of the long non-coding RNA LNC-POTEM-4 in cancer progression is limited. Our preliminary study found that LNC-POTEM-4 was overexpressed in hepatocellular carcinoma (HCC) tissues, which led us to further investigate the biological function and molecular mechanism of LNC-POTEM-4 in HCC development. LNC-POTEM-4 expression in HCC tissues was examined using transcriptome sequencing and quantitative reverse transcription PCR. The relationships between LNC-POTEM-4 and the stage and prognosis of HCC in patient data from the TCGA database were analyzed. The effects of LNC-POTEM-4 on proliferation, invasion/migration, and epithelial-mesenchymal transition marker expression in HCC cells were evaluated in vitro using gain- and loss-of-function assays, while its effects on tumor growth and metastasis were explored through animal experiments. A LNC-POTEM-4/microRNA (miR)-149-5p/Wnt4 regulatory signaling axis was identified using bioinformatics analysis, and dual luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Co-transfection of LNC-POTEM-4 and Wnt4 expression plasmids was employed to confirm the new signaling pathway. We found that LNC-POTEM-4 was overexpressed in HCC tissues and was linked to poor staging and prognosis. LNC-POTEM-4 promoted proliferation, invasion, migration, and the epithelial-mesenchymal transition of HCC cells in vitro. Silencing of LNC-POTEM-4 inhibited HCC growth and distant metastasis in vivo. Mechanically, LNC-POTEM-4 was found to function as a competitive endogenous RNA, upregulating Wnt4 by sponging miR-149-5p to promote HCC progression. Wnt4 overexpression may have counteracted the tumor-inhibition effect of LNC-POTEM-4 silencing. In conclusion, LNC-POTEM-4 upregulated Wnt4 to activate the Wnt signaling pathway and stimulate the malignancy tendency of HCC by sponging miR-149-5p, providing a prospective target for the detection and therapy of HCC. However, the effects of LNC-POTEM-4 on the miR-149-5p/Wnt4 signaling axis should be further studied in animal experiments.

Hepatocellular carcinoma (HCC), a major subtype of liver cancer, poses significant therapeutic challenges due to its late diagnosis and rapid progression. The evolving landscape of immunotherapy offers a beacon of hope, with natural killer (NK) cells emerging as pivotal players in combating HCC. NK cells are unique cytotoxic lymphocytes that are essential in the fight against infections and malignancies. Phenotypic and functional NK cell abnormalities have been shown in HCC patients, indicating their significance as a component of the innate immune system against cancer. This review elucidates the critical role of NK cells in combating HCC, focusing on their interaction with the tumor microenvironment, the development of NK cell-based therapies, and the innovative strategies to enhance their efficacy in the immunosuppressive milieu of HCC. The review delves into the various therapeutic strategies, including autologous and allogeneic NK cell therapies, genetic engineering to improve NK cell resilience and targeting, and the integration of NK cells with other immunotherapeutic approaches like checkpoint inhibitors and oncolytic virotherapy. By highlighting recent advancements and the ongoing challenges in the field, this review sets the stage for future research directions that could unlock the full potential of NK cell-based immunotherapy for HCC, offering a beacon of hope for patients battling this formidable cancer.

Objective

This study investigated whether Mulberryside A (MBA) can attenuate cigarette smoke extract (CSE)-induced autophagy through a Sirt1-dependent pathway, thereby attenuating atherosclerosis in ApoE−/− mice.

Methods

After treating human umbilical vein endothelial cells (HUVECs) with CSE and MBA, an MTT assay was performed to detect cell activity. Immunofluorescence and Western blotting were used to determine the expressions of autophagy-related proteins, Sirt1 and HIF-1α. Lentivirus and siRNA were used to construct overexpression and silencing (Sirt1 and HIF-1α) models. The in vivo inflammatory effects of CS on atherosclerosis in ApoE−/− mice were assessed by exposing mice to CS and MBA treatment. HE staining was used to detect atherosclerosis in mouse aortic tissue, and electron microscopy was used to detect autophagy of endothelial cells.

Results

CSE promoted autophagy in HUVECs, down-regulated Sirt1, and up-regulated HIF-1α expression. MBA treatment, overexpression of Sirt1, or silencing of HIF-1α attenuated CSE-induced autophagy, while MBA reversed CSE-induced downregulation of Sirt1 and upregulation of HIF-1α. However, overexpression of HIF-1α increased autophagy in HUVECs and attenuated the protective effect of Sirt1 overexpression or MBA on CSE-induced autophagy in HUVECs. In vivo experiments also demonstrated that MBA attenuates CS-induced aortic autophagy in ApoE−/− mice and up-regulates Sirt1 and downregulates HIF-1α expression.

Conclusions

MBA attenuates CSE-induced autophagy through the Sirt1-HIF-1α axis, thereby attenuating atherosclerosis in ApoE−/− mice.

Protein kinases, mediating their biological function via their catalytic activity, play important role in cell development, including cell proliferation, migration, angiogenesis and survival. Over the years, protein kinase inhibitors have been developed as an important class of anticancer agents clinically. However, the off-targeting and drug resistance of protein kinase inhibitors limit their efficiency. Anticancer peptides derived from marine organisms represent a novel class of bioactive substances, and some of the peptides exhibit anticancer effect via inhibiting protein kinases. In this mini review, the recent progress of anticancer peptides targeting protein kinases from marine sources are presented. Marine peptides inhibiting resistant cancer cells by targeting novel domains of protein kinases are highlighted. The challenges and prospects of developing marine peptides as anticancer agents are also discussed.

Cardiomyopathy constitutes a global health burden. It refers to myocardial injury that causes alterations in cardiac structure and function, ultimately leading to heart failure. Currently, there is no definitive treatment for cardiomyopathy. This is because existing treatments primarily focus on drug interventions to attenuate symptoms rather than addressing the underlying causes of the disease. Notably, the cardiomyocyte loss is one of the key risk factors for cardiomyopathy. This loss can occur through various mechanisms such as metabolic disturbances, cardiac stress (e.g., oxidative stress), apoptosis as well as cell death resulting from disorders in autophagic flux, etc. Sirtuins (SIRTs) are categorized as class III histone deacetylases, with their enzyme activity primarily reliant on the substrate nicotinamide adenine dinucleotide (NAD (+)). Among them, Sirtuin 1 (SIRT1) is the most intensively studied in the cardiovascular system. Forkhead O transcription factors (FOXOs) are the downstream effectors of SIRT1. Several reports have shown that SIRT1 can form a signaling pathway with FOXOs in myocardial tissue, and this pathway plays a key regulatory role in cell loss. Thus, this review describes the basic mechanism of SIRT1-FOXOs in inhibiting cardiomyocyte loss and its favorable role in cardiomyopathy. Additionally, we summarized the SIRT1-FOXOs related regulation factor and prospects the SIRT1-FOXOs potential clinical application, which provide reference for the development of cardiomyopathy treatment.

Studies have shown that Small conductance Ca2 + −activated K+ (SK) channel are expressed in fibroblasts. We aimed to determine the expression of SK2 channels in cardiac fibroblasts during myocardial hypertrophy and investigate its relationship with fibrotic remodeling. Myocardial hypertrophy and fibrotic remodeling induced by transverse aortic constriction (TAC) were assessed by echocardiography, Masson's trichrome staining and Western blot. Knockdown and overexpression of the SK2 protein were used to assess relationship between SK2 expression in fibroblasts and myocardial fibrosis. There is a positive correlation between myocardial fibrosis and SK2 channel protein expression during the development of myocardial hypertrophy. The differentiation and secretion of fibroblasts in mice with cardiac hypertrophy are enhanced, and the expression of SK2 channel protein is increased. Manipulating SK2 levels in fibroblasts can either promote or inhibit their differentiation and secretory function. Knocking down SK2 reduces the up-regulation of TGF β1, p-Smad2/3/GAPDH, p-p38/GAPDH, p-ERK1/2/GAPDH, and p-JNK/GAPDH proteins induced by Ang II in cardiac fibroblasts without significantly affecting total protein levels. AAV9-SK2-RNAi injection in mice improves cardiac function. Collectively, our study suggests that the expression of the SK2 channel is significantly increased in fibroblasts of mice with myocardial hypertrophy, potentially impacting myocardial fibrosis remodeling via the TGF-β signaling pathway.

Hepatic gluconeogenesis plays a crucial role in maintaining glucose homeostasis and serves as a potential therapeutic target for type 2 diabetes, while its underlying mechanisms are not fully understood. This study elucidates the role of the deubiquitinase OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) in gluconeogenesis. We found that hepatic OTUB1 expression is reduced in both db/db mice and patients with type 2 diabetes. Deletion of hepatic OTUB1 significantly elevates fasting blood glucose levels and increases the expression of key gluconeogenic genes. Conversely, overexpression of OTUB1 in hepatocytes mitigates diabetic hyperglycemia and enhances insulin sensitivity. It is known that the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB) functions as an inhibitor of hepatic gluconeogenesis by interacting with forkhead box protein O (FOXO1) and glucagon receptor (GPCR), but its own modification mechanism remains unclear. Our findings indicate that OTUB1 interacts with YWHAB and deubiquitinates it through a catalytic process, which in turn suppresses gluconeogenesis. Therefore, OTUB1 plays a pivotal role in inhibiting hepatic gluconeogenesis, highlighting its potential as a therapeutic target for type 2 diabetes.